14-3-3sigma controls mitotic translation to facilitate cytokinesis.
14-3-3sigma controls mitotic translation to facilitate cytokinesis.
复制标题
DOI：
--
复制
发表时间：
2007
期刊：
影响因子：
64.8
通讯作者：
E. Wilker;M. V. van Vugt;Steven A Artim;Paul H. Huang;Christian P. Petersen;H. Reinhardt;Yun Feng;P. Sharp;N. Sonenberg;F. White;M. Yaffe
中科院分区：
文献类型：
--
作者：
E. Wilker;M. V. van Vugt;Steven A Artim;Paul H. Huang;Christian P. Petersen;H. Reinhardt;Yun Feng;P. Sharp;N. Sonenberg;F. White;M. Yaffe
14-3-3蛋白在多种细胞反应中是至关重要的，包括细胞周期进程、DNA损伤检查点和细胞凋亡。一种特殊的14-3-3同种型，sigma，是p53应答基因，其功能在人类肿瘤中经常丢失，包括乳腺癌和前列腺癌，这是由于14-3- 3 sigma启动子的超甲基化或诱导特异性靶向14-3- 3 sigma的蛋白酶体降解的雌激素应答泛素连接酶。14-3-3sigma蛋白的丢失不仅发生在肿瘤本身，而且发生在周围的发育异常前组织（所谓的现场癌变），表明14-3-3sigma可能具有重要的肿瘤抑制功能，在肿瘤演变过程中早期丢失。14-3-3sigma的肿瘤抑制功能的分子基础是未知的。在这里，我们报告了一个以前未知的功能14-3-3sigma作为有丝分裂翻译的调节器，通过其直接的有丝分裂特异性结合到各种翻译/起始因子，包括真核起始因子4 B的化学计量方式。与正常细胞形成鲜明对比的是，缺乏14-3-3sigma的细胞不能抑制帽依赖性翻译，并且在有丝分裂期间和之后立即不刺激帽非依赖性翻译。这种翻译机制中的缺陷开关导致内源性内部核糖体进入位点（IRES）依赖性形式的细胞周期蛋白依赖性激酶Cdk 11（p58 PITSLRE）的有丝分裂特异性表达减少，导致胞质分裂受损，Polo样激酶-1在中间体的丢失和双核细胞的积累。14-3- 3sigma缺失细胞的异常有丝分裂表型可以通过p58 PITSLRE的强制表达或通过使用雷帕霉素在有丝分裂期间消除帽依赖性翻译和增加帽非依赖性翻译来挽救。我们的研究结果表明，在缺乏14-3-3sigma的情况下，异常的有丝分裂翻译如何损害有丝分裂退出以产生双核细胞，并提供了一个潜在的解释14-3- 3sigma缺陷细胞如何在非整倍体和肿瘤发生的道路上发展。
14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, sigma, is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3sigma promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3sigma for proteasomal degradation. Loss of 14-3-3sigma protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3sigma might have an important tumour suppressor function that becomes lost early in the process of tumour evolution. The molecular basis for the tumour suppressor function of 14-3-3sigma is unknown. Here we report a previously unknown function for 14-3-3sigma as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3sigma, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3sigma-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis.